DESCRIPTION (Investigator abstract): Over the past several years the concept of synaptic transmission in the central nervous system (CNS) has changed dramatically. Recent studies have shown that the response of a neuron to a specific afferent input may vary depending on which neurochemical messengers are present in the local microinvironment of the cell68. This variability of responsiveness suggests that neural circuits have the capacity for functional plasticity that is mediated through various neurqrndulators such as peptides and monnamines. Corticotropin releasing factor [CRF) is a peptide which is most commonly associated with the stress rest. However, recent studies have shown that this peptide has a widespread distribution in extrahypothalamic circuits, suggesting that it has a-broader role in controlling neural circuitry, in addition to its role in the stress axis. A second CNS system that has a high level of CRF input is the cerebellum. The cerebellum, which controls and coordinates movement, can be divided into two interrelated regions - the cortex and the nuclei. The distribution and function of CRF has been well documented in the cortex. Virtually nothing is known about the role of CRF in the nuclei. In addition to peptidase, other chemical agents have been shown to modulate neuronal activity such as monoamines. However, few studies have been carried out to analyze interactions between different neuromodulstors. In the proposed experiments we will use retrograde tracing techniques combined with immunohistochemistry at the light end electron microscopic level, as well as physiological recording techniques to test the hypothesis that the output of the cerebellum, as relayed by neurons in the cerebellar nuclei, will be determined not only by the amino acid transmitters released by both extrinsic and intrinsic afferents that synapse on the cells, but also by complex interactions of neuromodulators that are present in afferents derived from specific brainstem nuclei. The Specific Aims will address the following questions: I) What are the origins of CRF afferents in the cerebellar nuclei? 2) What proportion of CRF afferents collateralize to both the cerebellar cortex and nuclei? 3) What are the cytological characteristic and synaptic relationships of CRF terminals in the cerebellar nuclei? and 4) What are the physiological effects CRF on different populations of nuclear neurons? Movement disorders that involve diseases of the cerebellum are more severe and less likely to show compensation if the neurons in the cerebellar nuclei are disrupted, indicating that these cells are critical for proper coordination of motor activity. The intent of this study is to determine how various neuromodulators mediate changes in the efficacy of synaptic transmission in the normal cerebellum. Although this study will focus on the cerebellum, the principles derived should increase our general understanding of how the brain is capable of adapting its responsiveness to continually changing conditions and in particular the role of CRF in mediating this functional plasticity in extrahypothaiamic circuits.